This research is to continue our investigations on the mechanism of DNA synthesis in normal and malignant cells. Our focus is to determine the role of zinc in DNA polymerization in vitro and the nature of the cellular requirement for zinc in DNA replication. In addition we have recently been studying the function of added divalent metal cations on the fidelity of DNA synthesis. The following studies will be carried out in the forthcoming year: (1) Further establish the role of zinc in catalysis by DNA polymerases from E. coli and from human placenta. (2) Study the changes in fidelity by substitution of the added divalent metal activator, Mg2 ion, with Ni2 ion, Co2 ion or Mn2 ion. (3) Study the mechanism by which mutagenic and/or carcinogenic non-activating metal cations alter the fidelity of DNA synthesis in vitro. (4) Establish whether changes in the fidelity of DNA synthesis can be used to prescreen for mutagens and/or carcinogens.